Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) in Psoriasis: A Randomized Clinical Trial.

Importance: New, effective, and well-tolerated oral therapies are needed for treating psoriasis. Zasocitinib, a highly selective allosteric tyrosine kinase 2 (TYK2) inhibitor, is a potential new oral treatment for this disease.

Objective: To assess the efficacy, safety, and tolerability of zasocitinib in patients with moderate to severe plaque psoriasis.

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.

TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity.

Stromal Notch ligands foster lymphopenia-driven functional plasticity and homeostatic proliferation of naive B cells.

In lymphopenic environments, secondary lymphoid organs regulate the size of B and T cell compartments by supporting the homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain incompletely understood. To evaluate homeostasis of the mature B cell pool during lymphopenia, we turned to an adoptive transfer model of purified follicular B cells into Rag2-/- mouse recipients.

First-in-Human study of JNJ-55920839 in healthy volunteers and patients with systemic lupus erythematosus: a randomised placebo-controlled phase 1 trial.

Background: Activation of the type I interferon (IFN) pathway is associated with systemic lupus erythematosus (SLE). We assessed the safety and tolerability of JNJ-55920839, a human monoclonal antibody that selectively neutralises most human IFNα subtypes and IFNω, in healthy participants and those with SLE.

Methods: This was a two-part, first-in-human, phase 1, randomised, double-blind, placebo-controlled, multicentre study of single-ascending intravenous doses of 0·3-15 mg/kg or a single subcutaneous dose of 1 mg/kg JNJ-55920839 administered to healthy participants (part A) and multiple intravenous doses of 10 mg/kg JNJ-55920839 administered to participants with SLE (part B).

Reduced risk of mortality associated with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment and Registry (PSOLAR): A nested case-control analysis.

Background: The effects of systemic therapy on mortality risk among patients with psoriasis are not fully understood.

Objective: To evaluate the impact of systemic treatment on mortality risk in patients enrolled in the Psoriasis Longitudinal Assessment and Registry.

Methods: Nested case-control analyses were performed to estimate mortality risk.

Serious infections in patients with self-reported psoriatic arthritis from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) treated with biologics.

Background: Patients with psoriatic arthritis (PsA) have increased risk of adverse events, including serious infections (SI), compared with psoriasis patients.

Methods: Patients eligible for, or receiving conventional systemic and biologic agents for psoriasis were followed prospectively using PSOLAR. Cohorts included: ustekinumab, tumor necrosis factor (TNF) inhibitors; infliximab; etanercept; adalimumab; non-biologic/methotrexate (MTX) (reference group); and non-biologic/non-MTX.

Non-Melanoma Skin Cancer Risk Among Patients in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

To the Editor: Patients with psoriasis are at increased risk of developing non melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).1,2 The risk is especially elevated among those who previously received systemic treatment or phototherapy.2 Systemic treatments, including biologic therapies and methotrexate (MTX), are effective in managing immune-mediated diseases; however, they may increase susceptibility to NMSC due to immunosuppression or other factors.

Demography, baseline disease characteristics, and treatment history of psoriasis patients with self-reported psoriatic arthritis enrolled in the PSOLAR registry.

Background: To evaluate demographics, family history, and previous medication use at enrollment in a subset of psoriasis patients with self-reported psoriatic arthritis (PsA) enrolled in Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Methods: PSOLAR is an international, prospective, longitudinal, disease-based registry that collects data in patients receiving, or are eligible to receive, systemic or biologic treatments for psoriasis. Baseline demographic, disease characteristics, medical history, and prior medication use at enrollment were evaluated in PSOLAR psoriasis patients self-reporting PsA ( = 4315); a subset of which had their diagnosis of PsA established by a healthcare provider (HCP;  = 1719); patients with psoriasis only ( = 7775); and the overall PSOLAR population ( = 12,090).

Gastrointestinal Signs and Symptoms Related to Inflammatory Bowel Disease in Patients With Moderate-to-Severe Psoriasis.

Background: Psoriasis (PsO) is a chronic inflammatory skin disorder that may be associated with comorbidities, including inflammatory bowel disease (IBD), given common immunopathogenic mechanisms. Whether PsO patients are more likely to suffer from gastrointestinal (GI) signs and symptoms has not been well-characterized. Understanding their prevalence in PsO patients may inform strategies to evaluate for GI signs and symptoms, screen for those at risk for IBD, and guide choice of therapy.

Effect of Age of Onset of Psoriasis on Clinical Outcomes with Systemic Treatment in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Objective: Our objective was to compare therapeutic response among patients with early-onset psoriasis (EOP) and late-onset psoriasis (LOP) receiving adalimumab, etanercept, infliximab, ustekinumab, or methotrexate in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Methods: Patients were grouped by age of onset: EOP (age ≤ 40 years) or LOP (age > 40 years). Repeated-measures analysis with logistic regression was used to calculate the adjusted odds ratio (AOR; adjusted for baseline characteristics) for achieving a Physician's Global Assessment score of cleared/minimal (PGA 0/1) or a percentage of body surface area involved with psoriasis < 3% (%BSA < 3) or %BSA < 1 for all patients; similar sensitivity analyses were performed for each treatment group.

Biological treatment for psoriasis and the risk of herpes zoster: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

To describe the risk of herpes zoster (HZ) in patients with psoriasis and its relation to non-biologic systemic therapies or biologic treatment. Psoriasis Longitudinal Assessment and Registry (PSOLAR) is an international, prospective, registry that follows adult patients with psoriasis eligible to receive non-biologic systemic therapies or biologic therapies. Mutually exclusive therapy cohorts were defined.

Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Background: Patients with psoriasis are at an increased risk for depression. However, the impact of treatment on this risk is unclear.

Objective: Evaluate the incidence and impact of treatment on depression among patients with moderate-to-severe psoriasis.

Evaluation of Risk of Major Adverse Cardiovascular Events With Biologic Therapy in Patients With Psoriasis.

Background: Psoriasis is associated with increased risk of major adverse cardiovascular events (MACE).

Objectives: Compare MACE risk with biologics vs topical/phototherapy use.

Methods: Psoriasis Longitudinal Assessment Registry (PSOLAR) is an international psoriasis registry of patients eligible to receive biologic/systemic treatments prospectively.

Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry.

Background: The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood.

Objective: Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Methods: Nested case-control analyses were performed among patients with no history of malignancy.

Pregnancy-associated morphea: a case report and literature review.

Morphea, also known as localized scleroderma, is arare fibrosing disorder of the skin, the pathogenesisof which is incompletely understood. It is thought,however, to involve interplay of genetic dispositionand triggering environmental factors, such asinfections and autoimmunity. Pregnancy as a potentialtrigger has only been reported in four cases.

Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ.

B-Raf(V600E) inhibitors have been suggested to promote tumor regression with the help of host immunity, but this hypothesis has not been examined directly in detail. In this study, we profiled immunologic changes in the tumor microenvironment and tumor-infiltrating lymphocytes (TIL) in a B-RafV600E/Pten-driven murine model of melanoma after administration of the B-Raf(V600E) small molecule inhibitor PLX4720. In this model, we found that as tumors developed, they gradually acquired immunosuppressive features, including accumulation of regulatory T cells (Treg) and CD11b(+)/Gr-1(+) myeloid cells and loss of Th1 effector functions on CD4(+) TILs, such as CD40L and IFNγ expression.

Hypertrophic lupus erythematosus: the diagnostic utility of CD123 staining.

CD123-positive plasmacytoid dendrocytes are prominent in the infiltrate of discoid lupus erythematosus (LE). We hypothesized that these cells would also be present in hypertrophic LE and would aid in the histopathologic distinction from squamous cell carcinoma (SCC) and hypertrophic actinic keratosis (AK). Five cases of hypertrophic LE and 10 cases each of SCC and hypertrophic AK were stained with CD123.

Notch activity synergizes with B-cell-receptor and CD40 signaling to enhance B-cell activation.

How diverse environmental cues are integrated to regulate B-cell activation and development remains poorly understood. Here we show that Notch activity synergizes with B-cell receptor (BCR) and/or CD40 signaling to enhance several aspects of B-cell activation and function. We find that costimulation of follicular B cells with the Notch ligand Delta-like-1 leads to significant increases in BCR- and CD40-mediated proliferation and enhances production of IgG1(+) cells in vitro and in vivo.

Generation of peripheral B cells occurs via two spatially and temporally distinct pathways.

We have identified a population of newly formed bone marrow (BM) B cells that shares multiple characteristics with late transitional B cells in the spleen. Both late splenic transitional B cells and cells within this uncharacterized BM population expressed the cell-surface phenotype AA4(+) CD23(+), yet the developmental kinetics and the renewal rate of AA4(+) CD23(+) BM B cells mirrored recently formed BM B cells. Further, unlike the least mature B cells in the BM and spleen, AA4(+) CD23(+) BM B cells expressed the homing receptor CD62L, were dependent on the antiapoptotic cytokine receptor BR3 and the tec family kinase Btk, and proliferated in response to IL-4 plus CD40 stimulation.

Regulation of peripheral B cell maturation.

Although it is clear that the final phases of B cell maturation occur after newly formed B cells exit the bone marrow, the mechanisms underpinning the maturation, selection, and long-term survival of immature peripheral B cells remain poorly understood. Here, we review recent advances in our understanding of how B cell receptor (BCR)-mediated signaling events integrate with additional environmental cues to promote the selection and differentiation of immature B cells into functionally distinct subpopulations of mature B cells. We pay particular attention to the role of the Baff cytokine family and the Notch receptor-ligand family and their unique roles in promoting B cell survival and differentiation into follicular and marginal zone B cells.

Development and selection of edited B cells in B6.56R mice.

Tolerance to dsDNA is broken in mice with a high-affinity anti-DNA H chain transgene, 56R, on the C57BL/6 background (B6.56R). B6.

Characterization of marginal zone B cell precursors.

Selection of recently formed B cells into the follicular or marginal zone (MZ) compartments is proposed to occur by way of proliferative intermediates expressing high levels of CD21/35 and CD23. However, we show that CD21/35(high) CD23(+) splenocytes are not enriched for proliferative cells, and do not contribute substantially to the generation of follicular B cells. Instead, ontogenic relationships, steady-state labeling kinetics, and adoptive transfer experiments suggest that CD21/35(high) CD23(+) splenocytes serve primarily as precursors for MZ B cells, although their developmental potential seems to be broader and is influenced by environmental cues that are associated with lymphopenia.